Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study

Abstract

Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose-response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8-31.5). At thyroid radiation doses >20 Gy, a downturn in the dose-response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.

Malignant and benign thyroid nodules after total body irradiation preceding hematopoietic cell transplantation during childhood

“…Most of the cancers observed are papillary carcinoma and its follicular variants, with no observed systemic metastasis and the probability of developing metastatic disease is small in these patients. Exposure to low-dose ionizing irradiation of the head and neck has been shown to be associated with an increase in the incidence of thyroid nodules and carcinoma during childhood (11,13,16). However, the level of excess risk remains unclear, as not all the population systematically underwent ultrasound screening and some were not screened at all.…”

“…The nodules were bilateral in eight (38%) of the 21 patients. Nodule diameter ranged from 6 to 40 mm, with a median value of 13.7 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) mm.…”

“…The reported relative risks for thyroid nodules among the survivors of pediatric cancers who have undergone radiation therapy vary greatly, with an incidence of malignancy of 10-40% (6,7,8,9,10,11,12,13). Analysis of studies evaluating thyroid carcinoma after exposure to external radiation during childhood showed that the dose-response relationship was linear, although the risk appeared to plateau at the highest dose, with risk appearing to slightly decrease at doses of even more than 2000 cGy (9,11,13,14,15,16). Age at irradiation, sex, and duration of follow-up have also been identified as determinants influencing the risk of thyroid tumors.…”

“…Most of these studies included patients with Hodgkin disease and non-Hodgkin lymphoma or patients treated by cranial and craniospinal radiotherapy for acute lymphoblastic leukemia (17,18,19,20). However, the risk of malignancy following radiation exposure seems to depend not only on the dose of radiation administered but also on the type of the first cancer, the type of chemotherapy used, and the resulting immunodeficiency and/or associated autoimmune disorders (16,21). Only a few studies have investigated survivors who received total body irradiation (TBI) for hematopoietic stem cell transplantation (HSCT).…”

Oncology protocols: how can we do better?

“…Monitoring for recurrent disease and for development of second malignancies is ongoing for several years after treatment completion [6,14,15]. These regimens are typically tailored to salvage rates of relapse disease but vary widely among institutions and cooperative groups.…”